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The Sakigake designation system (Sakigake) has been launched to encourage the pioneered development of innovative new medical products for the effective treatment of severe illness in Japan, which allows leveraging the several advantages in prioritized consultation, rapid review, premium drug pricing and extended data-protection period. We retrospectively analysed the Sakigake products including drugs and regenerative medical products to clarify the achievements and the future issues in this system. From April 2015 to August 2020 (the first 5-year trial period of Sakigake), 37 products were designated, and 10 of those were approved in Japan in which 7 new active substances achieved the first-in-world approvals. Oncology, neurology and cardiovascular disease were the major therapeutic areas, and those 3 accounted for 75.7% of all products. Sakigake achieved some first-in-world approvals by the Pharmaceuticals and Medical Devices Agency/the Ministry of Health, Labor and Welfare of innovative new medical products, although in some therapeutic areas, there remains room in stimulating drug development.

The Pharmaceuticals and Medical Devices Agency (PMDA) has approved hundreds of new drugs in recent years. We retrospectively analyzed the new drugs approved in Japan from 2008 to 2019, and identify the first-in-world approvals and clarify the current drug lag. The new drug and the drug lag were defined as a drug with a new active substance and a difference between the approval date in Japan and the international birth date, respectively. Among 400 new drugs approved in Japan during the last 12 years, 80 (20.0%) were first approved in Japan, and 320 were outside Japan (the United States: 202, 50.5%; Europe: 82, 20.5%; other regions: 36, 9.0%). Of these, 45 new drugs have not yet been approved outside Japan, and the remaining 355 have been globally approved in Japan and overseas. The number of new drug approvals were the largest in oncology followed by metabolic/endocrine and infectious diseases. The median drug lags (year) among all 400 new drugs and 355 new drugs with global approvals were 4.3 and 4.7 in the first tertile (2008-2011), 1.5 and 2.6 in the second tertile (2012-2015), and reduced to 1.3 and 2.2 in the third tertile (2016-2019), respectively. Substantial drug lag remains in neurology, psychiatry, and therapeutic areas where the number of new drug approvals was relatively small. Collectively, one-fifth of the new drugs approved in Japan are first-in-world approvals. Drug lag has been greatly decreased, although it still exists.

Introduction To assess the efficacy of combined therapy involving bland transarterial embolization using gelatin sponge particles (bland GS-TAE) followed by transarterial chemoembolization using lipiodol mixed with anticancer agents and GS particles (Lip-TACE) to reduce the adverse events and increase the therapeutic effect of Lip-TACE in the treatment of huge (≥10 cm) hepatocellular carcinoma (HCC). Material and methods Twenty-one consecutive patients with huge HCCs (≥10 cm in diameter) were enrolled in this study. First, bland GS-TAE was performed to reduce the tumor volume, and then Lip-TACE was performed to control the remaining tumor at intervals of around three weeks. Tumor response, survival, and adverse events of this combined therapy were assessed. Results The tumor response was assessed three months after combined TACE, with complete response in 38.1% and partial response in 57.1% of cases. Severe adverse events were seen in two patients, acute cholecystitis and tumor rupture. The median survival time was 2.7 years, and the one-, two-, three-, and five-year overall survival rates were 76.2%, 66.7%, 42.9%, and 25.0%, respectively. Conclusion Combined therapy involving bland GS-TAE followed by Lip-TACE can be performed safety and may improve survival in patients with huge HCCs.

AIMS To clarify the rationales of delay or difference in the review of new drug applications among regulatory authorities for new drugs, those first approved in the world being in Japan. METHODS Among 80 new drugs first approved in Japan from 2008 to 2019, we identified those subsequently approved in the USA or Europe. Significant delays in approval time (boxplot outliers) and the rationales for the delays were assessed among the Pharmaceuticals and Medical Devices Agency (PMDA), the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). RESULTS Of the 80 Japan-first approvals, 25 and 24 were approved in the USA and Europe, respectively, and their median approval times in Japan, the USA and Europe were 285, 334 and 477 days, respectively. Significant delays were identified for pirfenidone (1806 days, FDA), alogliptin benzoate (1856 days, FDA), insulin degludec (1457 days, FDA) and romosozumab (750 days, PMDA; 994 days, FDA; 748 days, EMA). Due to concerns about cardiovascular risk, alogliptin benzoate and insulin degludec were requested for additional clinical trials by the FDA, and romosozumab required a much longer review period than the standard approval time in all three regions. CONCLUSIONS Among the new drugs significantly delayed in approval time in Japan, the USA or Europe, there were some differences in the requirements, the participating regions and the assessment of clinical trials. The regulatory views on the cardiovascular risk also differed among the three regions. These divergences may be associated with the differences in approval histories.

We aimed to analyze clinical features and treatment outcomes of otitis media caused by antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), i.e. otitis media with AAV (OMAAV).This survey was performed between December 2013 and February 2014. The study began with a preliminary survey to 123 otolaryngology institutions in Japan to inquire about their experiences with OMAAV patients during the past 10 years, and was followed by a questionnaire survey to investigate clinical and laboratory findings. OMAAV was defined using the criteria described in the text.Two hundred and thirty-five patients classified as OMAAV were enrolled in this study. They were characterized as follows: (1) disease onset with initial signs/symptoms due to intractable otitis media with effusion or granulation, which did not respond to ordinary treatments such as antibiotics and insertion of tympanic ventilation tubes, followed by progressive hearing loss; (2) predominantly female (73%) and older (median age: 68 years); (3) predominantly myeloperoxidase (MPO)-ANCA-positive (60%), followed by proteinase 3 (PR3)-ANCA-positive (19%) and both ANCAs-negative (16%); (4) frequently observed accompanying facial palsy (36%) and hypertrophic pachymeningitis (28%); and (5) disease often involving lung (35%) and kidney (26%) lesions. Four factors associated with OMAAV were found to be related to an unfavorable clinical course threatening the patient's hearing and/or lives, namely facial palsy, hypertrophic pachymeningitis, both ANCAs-negative phenotype, and disease relapse. The occurrence of hypertrophic pachymeningitis was associated with facial palsy (p 0.05), both ANCAs-negative phenotype (p 0.001), and headache (p 0.001). The administration of corticosteroid together with an immunosuppressant was an independent predicting factor for lack of disease relapse (odds ratio [OR] = 1.90, p = 0.03) and an improvement in hearing loss (OR =2.58, p = 0.0002).Since OMAAV has novel clinical features, the disease may be categorized as a subentity for the classification of AAV.

Purpose As stereotactic radiotherapy (SRT) becomes widespread, precise information including number, location, and margin of lesions is required when magnetic resonance (MR) imaging of brain metastasis is performed. We compare methods using 2 separate injections and a single injection for the administration of a double dose of contrast medium for contrastenhanced MR imaging. Materials and methods We divided 40 patients with brain metastasis into 2 groups of 20 patients. Group A received 2 separate injections (0.2 + 0.2 mL/kg) of contrast medium (gadoteridol); Group B received a single injection of the same total dose (0.4 mL/kg). Group A underwent spin echo (SE) T1-weighted imaging (T1WI) and magnetization prepared rapid acquisition with gradient echo sequence (MPRAGE) after each injection, and Group B underwent the same MR studies at the same timing as Group A. We evaluated the number, signal-to-noise ratio (SNR), diameter, margin delineation, and volume of lesions and compared them between early and delayed studies by the 2 methods. Results The number of detected lesions was largest in delayed studies of MPRAGE in both groups. The SNR of the lesions was statistically lower in early studies of Group A than other studies. Delayed studies of Group B showed statistically better margin delineation than other studies on both SE-T1WI and MPRAGE studies. Diameter and enhanced volume were statistically significantly larger on delayed phase than early phase in both groups. Conclusion Use of a single injection of double-dose contrast medium and longer delay time may improve margin delineation of lesions for the study of brain metastasis. Enhanced volume was larger on delayed phase, and it may influence selection of therapeutic strategy.

The purpose of this pilot study was to assess the effectiveness of repeated bland-TAE using small-size microspheres for liver metastases. To date, there have been no publications as to whether bland-TAE could be effective for nonhypervascular liver tumors.Bland-TAE with 100-μm, calibrated microspheres was performed in two chemoresistant patients: one with colorectal metastases and the other with gastric metastases. Both patients had multiple tumors in the entire liver. An implantable port-catheter system was placed in the hepatic artery to conduct repeated embolizations, thereby achieving enough efficacies. Microspheres were injected via the port until the disappearance of the tumor stains. Angiographies via the port were conducted 1, 3, 7, and 14 days after bland-TAE to evaluate the patency of the hepatic artery.The hepatic artery started to recanalize 1 day after TAE and tumor stains appeared again during the 14 days. In both patients, bland-TAE was repeated four times in intervals of 14-21 days. The enhanced CTs showed necrotic changes and the decrease in size of the tumors. The serum CEA level decreased from 2,989 to 70 ng/ml and from 174 to 48 ng/ml, respectively. Bilomas and a liver abscess developed as complications.Repeated bland-TAE using 100-μm microspheres injected via an implantable port-catheter system could be effective for liver metastases, although the caution of biliary injury is needed.

Purpose This multicenter prospective study was conducted to evaluate the safety and the efficacy of uterine artery embolization (UAE) with gelatin sponge for symptomatic leiomyomas. Materials and Methods Patients with symptomatic uterine leiomyomas were enrolled and treated with UAE. In phase I, nine patients were evaluated for safety. In phase II, 24 patients were accrued, and an intent-to-treat analysis was performed on all 33 patients. The primary endpoint was safety. Secondary endpoints included technical success, hospital stay, change in symptoms, leiomyoma volume on magnetic resonance (MR) imaging, and incidence of treatment failure. Results UAE procedures were performed for all 33 patients. Two patients were lost to follow-up at 3 and 12 months. The median follow-up period was 33.4 months. Minor adverse events (AEs) occurred in 10 patients (33%); major AEs of permanent amenorrhea and leiomyoma expulsion occurred in two (6%). The most common AE was transient amenorrhea. Technical success was achieved in all patients. The median hospital stay was 5 days. At 12 months after UAE, menorrhagia had improved in 90% of patients, pelvic pain in 78%, and bulk-related symptoms in 97%. The mean reduction in leiomyoma volume on MR imaging at 12 months was 61%. Treatment failure occurred in one patient, who underwent hysterectomy for recurrent menorrhagia at 21 months. Conclusions UAE with gelatin sponge is safe, with efficacy comparable to other embolic agents based on published data. Gelatin sponge should be an option for UAE, but a prospective comparison versus other standard UAE embolic agents may be warranted.

Arterial infusion chemotherapy for unresectable pancreatic cancer may be an attractive strategy. We are currently developing a new interventional radiology technique to unify the pancreatic blood supply for chemoinfusion. In this article, we evaluated the feasibility, therapeutic potential, and limitations of this technique.Twenty-eight patients with advanced pancreatic cancer were retrospectively reviewed. After the superior mesenteric artery was embolized, the drug distribution to the tumor was evaluated by a unified CT angiography system.In all patients, tumors had dual arterial blood supplies from both the celiac and superior mesenteric arteries. Unification of pancreatic blood supply was successful in 14 patients (50%). The whole pancreatic tumor was exclusively supplied by the celiac artery in these patients. In the remaining 14 patients, a part of the tumor was still supplied by the superior mesenteric artery even after embolization. In most failed cases, the tumor had invaded to the root of the small-bowel mesentery or transverse mesocolon. By contrast, unification of the pancreatic blood supply could be achieved in cases invading to the stomach and duodenum. The whole liver was also successfully supplied by arterial infusion from the celiac artery after embolization.Our novel technique for arterial infusion chemotherapy is simple, feasible, and well tolerated. Furthermore, arterial chemoinfusion may be a breakthrough in selected patients with unresectable pancreatic cancer.

We report a case of cystic echinococcosis (CE) caused by Echinococcusgranulosus, for which a modified percutaneous evacuation (PEVAC) treatment was applied. The patient had immigrated from Peru to Japan and had 2 hydatid cystic masses, 1 located in segment (S)5 of the liver and the other in S3 (5.3 and 3.5 cm in diameter, respectively), both of which were visualized as pseudotumors by ultrasound (US) examinations. Albendazole treatment showed no effects and surgical treatment was refused. After punctuation of the S5 cyst under US guidance and S3 with CT guidance, 10- and 12-French gauge catheters, respectively, with multiple side holes were inserted. About 60 ml of the cyst contents was drawn out from the S5 lesion and 2 ml from the S3 lesion. Using repetitive manual injections and aspiration of small amounts of hypertonic saline, the remaining cyst content was removed as much as possible, after which 20 and 10 ml of 98% ethanol was injected into the S5 and S3 lesions, respectively. A short-term evaluation during the 4 month-period following the procedure using US revealed nearly complete evacuation of the S5 lesion, whereas that at S3 remained as a pseudo-solid mass. We consider that percutaneous treatment is a safe therapeutic modality for hydatid cysts. This is the first case report of CE treated percutaneously in Japan.

Systemic chemotherapy and chemoradiotherapy, the standard treatments, do not satisfactorily improve the poor prognosis of unresectable pancreatic cancer. The authors administered arterial infusion of 5-fluorouracil (5-FU) combined with concurrent radiation therapy to enhance the antitumor effect of chemotherapy. The purpose of this study was to examine the efficacy and safety of this combined therapy.One or two catheters were placed into the pancreas-supplying arteries angiographically. To obtain adequate drug distribution, the positions of the catheters were determined in accordance with the results of CT during arterial injection of contrast material. A dose of 333 mg/m2/d of 5-FU was continuously infused for 5 days a week for 5 weeks, with concurrent radiation therapy (50 Gy at 2.0 Gy per fraction). Twenty patients with unresectable pancreatic cancer were enrolled in this study.Of the 20 patients, 19 (95%) completed the scheduled course of this combined therapy. Fourteen patients showed a partial response (response rate, 70%). Serum cancer antigen 19-9 (CA 19-9) levels were reduced by more than 50% in 16 of 18 patients (80%). The 1-year and 3-year survival rates were 40% and 17%, respectively, with a median survival time of 11.0 months. Grade 3 or worse nonhematologic toxicity was observed in 11 patients (55%), but there were no life-threatening toxicities or complications.Arterial infusion of 5-FU combined with concurrent radiation therapy is tolerable and can produce a high response rate with encouraging survival duration for unresectable pancreatic cancer.

Previous reports have shown the effectiveness of adjuvant hepatic arterial infusion chemotherapy (HAIC) in pancreatic cancer. However, percutaneous catheter placement is technically difficult after pancreatic surgery. The purpose of this study was to evaluate the feasibility and outcome of HAIC using a coaxial technique compared with conventional technique for postoperative pancreatic cancer. 93 consecutive patients who received percutaneous catheter-port system placement after pancreatectomy were enrolled. In 58 patients from March 2006 to August 2010 (Group A), a conventional technique with a 5-Fr indwelling catheter was used and in 35 patients from September 2010 to September 2012 (Group B), a coaxial technique with a 2.7-Fr coaxial catheter was used. The overall technical success rates were 97.1 % in Group B and 86.2 % in Group A. In cases with arterial tortuousness and stenosis, the success rate was significantly higher in Group B (91.7 vs. 53.8 %; P = 0.046). Fluoroscopic and total procedure times were significantly shorter in Group B: 14.7 versus 26.7 min (P = 0.001) and 64.8 versus 80.7 min (P = 0.0051), respectively. No differences were seen in the complication rate. The 1 year liver metastasis rates were 9.9 % using the conventional system and 9.1 % using the coaxial system (P = 0.678). The overall median survival time was 44 months. There was no difference in the survival period between two systems (P = 0.312). The coaxial technique is useful for catheter placement after pancreatectomy, achieving a high success rate and reducing fluoroscopic and procedure times, while maintaining the safety and efficacy for adjuvant HAIC in pancreatic cancer.

Transcatheter embolization is considered to be less effective for early-stage hepatocellular carcinomas (HCCs) without a hypervascular arterial supply. In the present case report, a 65-year-old male with hepatitis type C and non-hypervascular HCC located in the hepatic hilum was successfully treated by bland transarterial embolization (TAE). After the temporary protective embolization of normal liver tissue using large gelatin particles, diluted 40-μm microspheres were injected via the tumor-feeding artery. The tumor shrank, and the patient has survived for 25 months without recurrence.

Purpose To compare the efficacy, complications, and inflammatory levels in partial splenic embolization (PSE) with coils or gelatin sponge (GS) particles with or without intraarterial antibiotic agents. Materials and Methods Forty-four patients with hypersplenism treated by PSE were assessed. GS particles were used in 31 patients, and coils were used in 13 patients. In 17 of the 31 patients who received GS, GS suspended in antibiotic solution was injected via the splenic artery. In the other 14 patients, antibiotic agents were not used. In all 13 coil group patients, an antibiotic solution was intraarterially injected before embolization. Platelet counts were compared between the GS and coil groups. Complications and serum C-reactive protein (CRP) levels were compared among the three groups. Results There were no significant differences in platelet counts and platelet increased ratios at 6 months (10.0 × 10 4 /µL and 193% in the GS group vs 9.0 × 10 4 /µL and 221% in the coil group), and no significant differences in frequencies of complications. However, one splenic abscess occurred in a patient treated with GS without antibiotics, resulting in death. The mean serum CRP level in the GS with antibiotic group at 2 weeks was significantly lower than in the other two groups. Conclusions The efficacy of PSE is similar with the use of coils versus GS particles. Prophylactic intraarterial antibiotic treatment could be useful in preventing inflammatory reactions after PSE.

BACKGROUND The aim of this study was to evaluate the safety and feasibility for single-incision laparoscopic cholecystectomy (SILC) by retrospective comparison with conventional laparoscopic cholecystectomy (CLC) in a local community hospital. METHODS SILC was introduced and performed in 57 patients for benign gallbladder diseases. Their clinical data were compared with those of 62 patients treated with CLC. They included patient demographic data and operative outcomes. RESULTS SILC was attempted in 57 patients and 52 cases (91.2%) were successfully completed. There were no statistical differences between the 2 groups in terms of operative time, blood loss, and postoperative complications. The length of hospital stay in the SILC group was significantly shorter compared with CLC (P < 0.0001). CONCLUSIONS SILC has been successfully introduced in a local community hospital. The safety and feasibility was also confirmed. The SILC procedure may become 1 standard option for the treatment of benign gallbladder diseases.

A 70-year-old man with liver cirrhosis due to hepatitis C viral infection had a single well-differentiated hepatocellular carcinoma(HCC) of 5-cm diameter in the right superior anterior segment of the liver. Surgery could not be performed because of his poor liver function. Furthermore, it was difficult to treat this tumor with transcatheter arterial chemoembolization because the tumor exhibited hypovascularity. Radiofrequency ablation (RFA) alone was also not an option because the tumor was too large to manage with a simple RFA procedure. This solitary tumor was adjacent to the right and middle hepatic veins. Finally, we planned to treat this tumor with RFA and temporary vessel occlusion as follows: RFA was performed with a 5-cm expandable type RITA model 90 electrode under temporary occlusions of the right anterior hepatic artery with degradable starch microspheres, and of the right and middle hepatic veins by balloon catheters, to reduce the heat sink effect and obtain a larger coagulation size. We successfully treated this HCC with RFA combined with temporary vessel occlusion, and the patient has not obtained local recurrence at 18 months of the procedure.

Miriplatin(MP) is a promising newly developed anticancer agent for transcatheter arterial chemoinfusion in patients with hepatocellular carcinoma(HCC), particularly those previously not treated with chemotherapy. The aim of this study was to assess the efficacy and safety of transarterial chemolipiodolization with MP for recurrent HCC in patients previously treated with chemotherapy.From January 2010 to March 2011, 17 patients with recurrent HCC were treated with MP via a transcatheter arterial approach. The dose of MP per treatment session was up to 140 mg. We repeated this treatment protocol until tumor progression occurred. We assessed the therapeutic results and the adverse events.MP was infused at a dose of 60-140 mg in the initial treatment session; the mean treatment session number was 1.8; and the total dose of MP was 60-400 mg (median, 120 mg). Response rate and disease control rate after the initial treatment were 17.6% and 47.1%,respectively. Response rate and disease control rate after the total treatment session were 17.6% and 29.4%,respectively. Median tumor-free survival was 86 days. We encountered a severe adverse event in 1 patient who died due to his concomitant disease( diabetic nephropathy and radiation hepatitis) 38 days after this protocol.The therapeutic result of MP was unsatisfactory, but adverse events due to MP infusion, including renal and/or liver damage, were minor.

To evaluate the feasibility of combining placement of a transjugular intrahepatic portosystemic shunt (TIPS) and transcatheter hepatic segmental artery chemoembolization with Lipiodol (Seg-Lp-TAE) in patients with cirrhosis, esophagogastric varices, and hepatocellular carcinoma (HCC).Five patients with bleeding or large, high-flow esophagogastric varices and HCC were treated by TIPS and Seg-Lp-TAE.The mean portosystemic pressure gradient decreased from 20.8 cm H2O to 7.8 cm H2O after TIPS. The direct portogram and endoscopic examination revealed reduction of varices. At 6 months, one shunt had functionally occluded and could not be reopened; the other TIPS remained functional. Follow-up CT and the changes of alpha fetoprotein indicated effective therapy of Seg-Lp-TAE for HCC. Four patients are in stabile clinical condition at 9, 6, 1, and 1 months after the combined therapy; one died after 14 months due to decompensated liver cirrhosis.The combined therapy of TIPS and Seg-Lp-TAE will become a new interventional approach for patients with HCC and esophagogastric varices.

Several cytokines are known to play roles in the pathogenesis of human glomerulonephritis. Recently, some studies proposed a possible relationship between interleukin-4 (IL-4) and glomerulonephritis. To investigate the involvement of IL-4 in human glomerulonephritis, we evaluated renal biopsy specimens using immunohistochemical procedures. Our study revealed that the glomeruli in immunoglobulin A nephropathy and lupus nephritis (World Health Organization grades II and IV) contained IL-4-positive cells, which were CD-3- and CD-4-positive T lymphocytes. CD-8-, CD-14-, CD-19-, or CD-56-positive cells did not react with anti-IL-4. CD-23-positive cells were not observed in the sections used in this study. Interleukin-4-positive cells were not found in the normal control kidney tissues. The degree of the glomerular IL-4-positive cell index correlated well with the glomerular hypercellularity index, but not with any other clinical or histopathologic parameters. Therefore, the present study offers more reliable evidence concerning the association between IL-4 and human glomerulonephritis.

We developed segmental Lp-TAE, which is transcatheter hepatic sub-subsegmental, subsegmental, or segmental chemoembolization using Lipiodol introduced into the tumor-bearing hepatic sub-subsegment, subsegment, or segment as the target area. A total of 98 patients with nonresectable hepatocellular carcinoma (HCC) undergoing segmental Lp-TAE (Seg-Lp-TAE) were studied, and the relationship between the CT pattern observed after Seg-Lp-TAE (Seg-Lp-CT) and the therapeutic results obtained in those patients was evaluated. Seg-Lp-CT was classified into four types (type I, homogeneous; type II, defective; type III, inhomogeneous; and type IV, only slight accumulation, if any) according to the Lipiodol accumulation pattern observed after Seg-Lp-TAE. The cumulative nonrecurrence rates of type I were higher than those of types II–IV. The cumulative survival rates of type Ia, in which Lp accumulation is also seen around the main tumor, were the highest (93.8% at 1 year, 85.9% at 2 years, 85.9% at 3 years, and 57.3% at 4 years). The cumulative survival rates achieved with Seg-Lp-TAE were 89.2% at 1 year, 69.4% at 2 years, 58.9% at 3 years, 44.0% at 4 years, and 30.2% at 5 years, which were higher than those achieved with conventional Lp-TAE. Seg-Lp-TAE is very useful in the treatment of HCC limited to one sub-subsegment, subsegment, or segment, and it is important to choose subsubsegmental, subsegmental, subsegmental, or segmental Lp-TAE on the basis of the size and site of the tumor as well as the type and the number of feeding arteries.

Electrocochleography using the transtympanic electrode technique was performed on 86 deaf ears. Auditory nerve action potential was detected in 9 ears, in 5 of which deafness was caused by cerebellopontine angle tumor or surgery. A low threshold of the cochlear microphonics' response was also observed in some of the cases with deafness caused by mumps or cerebellopontine angle tumor. Various pathophysiological states of the inner ear can be observed, even in cases showing the same total deafness when measured by audiometer.

Although chemoradiotherapy with full-dose gemcitabine as a strategy for locally advanced pancreatic cancer was expected to optimize local tumor control and prevent distant metastasis, the volume of the radiation field is the critical factor related to toxicities. We are currently developing a novel therapeutic technique to conduct neoadjuvant treatments of intra-arterial chemoinfusion prior to chemoradiotherapy with the aim of tumor volume reduction.In two patients with locally invasive pancreatic cancer, the pancreatic blood supply was altered under angiographic guidance, and an intra-arterial catheter with a subcutaneous port was left in place for the administration of 5-fluorouracil (5-FU) 1,000 mg/m(2). After shrinkage of the tumor, chemoradiotherapy with gemcitabine 1,000 mg/m(2) was delivered. In both patients, the full-dose gemcitabine was administered concurrently with radiation therapy without severe complications. The patients responded to the treatment with survival times of 42 and 38 months.Intra-arterial chemoinfusion followed by chemoradiation with full-dose systemic gemcitabine might prove to be a promising therapeutic approach for locally advanced pancreatic cancer. Large prospective Phase II trials of this combination regimen are warranted.

Acquired somatic mutations of JAK2 have been reported to play a pivotal role in the pathogenesis of BCR-ABL1-negative myeloproliferative neoplasm (MPN). However, the molecular characteristics of childhood MPN remain to be elucidated.We investigated a group of pediatric patients diagnosed either with essential thrombocythemia (ET; N = 9) or polycythemia vera (PV; N = 4) according to WHO criteria (median age = 10 years; range 1.5-15 years) in whom direct sequencing was performed for the existence of genetic alterations in JAK2, MPL, TET2, ASXL1, CBL, IDH1, and IDH2. More sensitive allele specific polymerase chain reaction was used for JAK2(V617F) genotyping.We found three patients harbor JAK2(V617F) mutation (2/9 ET and 1/4 PV). Bone marrow examination showed small and large megakaryocytes with dysplastic features in JAK2(V617F)-positive ET patients compared to those without JAK2(V617F). We identified a previously unrecognized missense mutation at codon 1230 in exon 12 of ASXL1 gene in ET and PV patients (1/9 ET and 1/4 PV). Otherwise, no genetic alterations could be detected in JAK2 exon 12, MPL, TET2, CBL, IDH1, and IDH2 in all ET and PV patients.Although JAK2 mutations in childhood ET and PV are not as frequent as reported in adult patients, JAK2 is the most frequently mutated gene in childhood MPN known so far. Owing to the presence of childhood MPN without any genetic alterations in JAK2, MPL, TET2, ASXL1, CBL, IDH1, and IDH2, new biological markers have to be found.

To clarify the efficacy of transcatheter hepatic sub-subsegmental, subsegmental, and segmental arterial chemoembolization using lipiodol (subseg/seg lip-TACE) for hepatocellular carcinoma (HCC), long-term outcomes of patients who had been treated using subseg/seg lip-TACE alone were retrospectively examined.Subjects comprised 199 patients with HCC (T1/2/≥3=30/108/61; Child-Pugh A/B/C=115/52/32; Japan Integrated Staging [JIS] score≤1/2/≥3=88/64/47) who underwent subseg/seg lip-TACE using lipiodol mixed with an anticancer drug followed by injection of gelatin sponge particles. Each patient was followed-up every 3 months, and repeat subseg/seg lip-TACE and/or conventional lip-TACE was performed in cases showing recurrence. One-, 3-, 5-, 7-, and 10-year cumulative survival rates were calculated. Subgroup analyses were performed by stratifying the population according to T-factor, Child-Pugh classification, and JIS score.Median duration of follow-up was 3.8 years (range 0.2 to 16.4). Median overall survival was 3.8 years. One-, 3-, 5-, 7- and 10-year survival rates were 91.5, 66.1, 38.8, 20.3, and 9.4% for all patients, and 95.5, 76.9, 51.9, 27.9 and 20.4% for patients with JIS≤1, respectively. Significant survival differences were found across two subgroups of staging systems (T2 vs. T3≤[P=0.0012] and JIS score≤1 vs. 2 [P=0.0036]).This study demonstrated that subseg/seg lip-TACE is a feasible treatment for obtaining prolonged survival in patients with localized HCC showing rich vasculature. Outcomes are influenced by both tumor stage and liver function, as seen in the best prolonged survival in patients with JIS score≤1.

We report a 60-year-old female with locally advanced pancreatic cancer successfully treated with stereotactic radiotherapy after arterial chemoinfusion. Using the indwelling catheter-port system with the unification of the pancreatic blood supply, we initially conducted an arterial infusion of weekly high-dose 5-FU (1,000 mg/m2/qw) combined with systemic gemcitabine (1,000 mg/m2/qw). As a result, the tumor was remarkably decreased. However, a part of the tumor where the drug had not been distributed remained in no reduction. Therefore, we added the stereotactic radiotherapy (50 Gy) targeted on the limited residual tumor and combined with concurrent systemic gemcitabine (1,000 mg/m2/qw). The residual tumors have been controlled well without distant metastases, and the patient is alive today 36 months after our initial treatment.

Transcatheter chemoembolization using Lipiodol (Lp) mixed with chemotherapeutic agents followed by Gelfoam particle injection only to the tumor-bearing hepatic segment (segmental Lp transcatheter hepatic artery embolization) (TAE) was applied to more than 100 patients with hepatocellular carcinoma and metastatic liver cancer. For segmental Lp-TAE, knowledge of the variations of intrahepatic arterial anatomy is important. Furthermore, the catheters and guidewires, volume of Lp, kinds and dose of chemotherapy, preparation of the mixture of Lp and chemotherapy (Lp-emulsion), method of injection of Lp-emulsion and Gelfoam particles, as well as the follow-up computed tomography examination are key items to the success of the procedure and are reviewed.

A patient with collagenofibrotic glomerulopathy associated with hepatic persinusoidal fibrosis is described. Renal biopsy revealed that the glomerular tufts contained homogeneous material that was proved by electron microscopy to be collagen fibers. The material was reactive to anti-type III collagen monoclonal antibody. Liver biopsy also showed an increase of type III collagen fibers in the perisinusoidal area. Since the serum procollagen III peptide level was elevated in this patient, fibrosis may have been simultaneously activated in kidney and liver by some unknown condition.

Brain abscess associated with an arteriovenous fistula (AVF) is sometimes difficult to diagnose and tends to recur. We report a case of recurrent brain abscess due to a pulmonary AVF (PAVF). A 69-year-old woman with a mass in the left cerebral peduncle had taken a progressively worse and shown decorticate rigidity. After an intravenous antibiotic for fever of unknown origin was changed, her condition gradually improved. She was discharged with the help of a cane. Thirty-one months later, she suffered left hemiparesis. Magnetic resonance imaging revealed a cystic mass in the right lateral frontal lobe. At surgery, we confirmed pus in the cyst. A PAVF was detected and was treated with coil embolization. The left hemiparesis improved and the postoperative course was uneventful. Exhaustive study is absolutely necessary to detect the etiology of recurrent brain abscess and to achieve a cure.

The purpose of this study was to investigate the potential pharmacokinetic advantage of pancreatic arterial infusion chemotherapy of 5-fluorouracil (5-FU) with temporary unification of the pancreatic blood supply for advanced pancreatic cancer in an animal model.Nine pigs were divided into three groups of three pigs each. 5-FU (20 mg/kg) was infused via jugular vein (group I), celiac artery (group II), and celiac artery with balloon occlusion of the superior mesenteric artery (SMA; group III). At 0, 10, 30, and 60 minutes after drug infusion, the concentrations of 5-FU were measured in plasma and tissues including the liver, pancreatic head, pancreatic uncinate process, and duodenum. Areas under the concentration-time curve (AUCs) were calculated and statistically compared.The temporary unification of the pancreatic blood supply by converting from dual blood supply through the celiac artery and SMA into a single celiac arterial supply was confirmed by dye injection. Mean AUCs in the pancreas head and liver were significantly higher for groups II and III compared with group I (P.05). In contrast, there were no significant differences in plasma 5-FU concentrations between groups. In addition, the AUC in the pancreatic uncinate process was significantly higher for group III compared with groups I and II (P.05).Pancreatic arterial infusion chemotherapy allows efficient regional drug delivery into the pancreas and liver. Importantly, the unification of the pancreatic blood supply may be required to induce maximum efficacy of arterial infusion chemotherapy for the tumor in the pancreatic uncinate process.

The purpose of this study was to investigate whether diffusion-weighted magnetic resonance imaging (DWI) is useful for early detection of the response of hepatic colorectal metastases to hepatic arterial infusion chemotherapy (HAIC) with 5-fluorouracil (5-FU). The subjects were 12 patients with hepatic colorectal metastases. The indwelling catheter for HAIC was placed in the hepatic artery, and 1000 mg/m2 5-FU was given repeatedly once a week. DWI was performed before and 9 days after HAIC. The minimum and mean apparent diffusion coefficient (ADC) values (minADC and meanADC) were measured. The relative change in ADC values (%ADC) and the relative change in tumor size on follow-up CT after 3 months (reduction ratio) were determined. Liver metastases were divided into two groups, responder and nonresponder. The correlation between %ADC and reduction ratio was determined, and %ADC was compared between the two groups. Eleven patients successfully completed HAIC over the 3-month period; 48 metastatic lesions were evaluated. Positive correlations were observed for relative change between %minADC and reduction ratio (r = 0.709) and between %meanADC and reduction ratio (r = 0.536). Both %minADC and %meanADC were significantly greater in the responder group than in the nonresponder group. With the threshold determined as < 3.5%, the receiver-operating curve analysis showed higher sensitivity and specificity values for %minADC (100% and 92.6%, respectively) than for %meanADC (66.7% and 74.1%, respectively). In conclusion, the relative change in minimum ADC values on DWI may be useful for early detection of the response of liver metastases to HAIC with 5-FU.

We describe herein a patient who had hepatic metastases with an arteriovenous shunt and was treated by hepatic arterial infusion chemotherapy. The arteriovenous shunt was diagnosed by (99m)Tc-macroaggregated albumin scintigraphy and hepatic venous embolization was performed to reduce shunt flow.

To retrospectively clarify the utility of metallic stent placement for the treatment of the malignant obstruction of the superior vena cava (SVC) in 71 patients with VC syndrome (SVCS) on the basis of long-term follow-up data. Seventy-one patients underwent stent placement and were followed until death. The applicability of the spiral Z-stent (S-Z-stent) mainly used the initial and follow-up results, stent placement for bilateral BCV obstruction and the value of concurrent anticancer therapy were studied. The technical success rate was 100%, the initial clinical success rate was 87% (62/71), the primary clinical patency rate was 88% (57/65), and the secondary clinical patency rate was 95% (62/65). The obstruction rate of the stent was 12% (8/65), and an additional stent was useful for relief of recurrent SVCS. Survival of 57 patients in whom there was no recurrence of SVCS until death ranged from 1 week to 29 months (mean, 5.4 months and the S-Z-stent appeared to be suitable for the treatment of the malignant obstruction of SVC. Unilateral stent placement was effective for relief of SVCS with bilateral BCV obstruction. Patients who received concurrent anticancer therapy survived 2 months longer than those who did not. Stent placement is an effective treatment for SVCS. Further, the utility of S-Z-stent for SVCS, an additional stent for recurrence, unilateral stent for patients with bilateral BCV obstruction, and anticancer therapy after stent placement were verified.

We evaluated the efficacy of ethanolamine oleate (EO) as a sclerosing agent for a symptomatic hepatic or renal cyst. Seven patients with symptomatic hepatic (n = 3) or renal cysts (n = 4) were treated by sclerotherapy with EO. The cyst size in the greater diameter ranged from 6 to 13 cm. The cyst was punctured under ultrasound guidance, and after all of the cyst’s content was aspirated, an iodized contrast agent was injected to check the absence of communication between the cyst and biliary tree, urinary tract, or vessels. Then, the solution of ethanolamine oleate–iopamidol mixture (EOI) of 10% of the volume of the cyst’s content was injected via catheter. After 30 min, the injected EOI was aspirated completely before catheter removal. A follow-up computed tomography scan was performed at 1 and 3 months after treatment. The volume of the cyst and its reduction rate was calculated. In addition, symptoms and complications were assessed. The volume of the cyst ranged from 64 to 636 ml (mean: 328 ml) before treatment. Three months after treatment, it ranged from 2 to 50 ml (mean: 15ml) and the reduction rate of the cyst’s volume was more than 90% on average. Symptoms caused by the cyst disappeared in all cases and no major complication was encountered. Although two patients had a low-grade fever after sclerotherapy, it was easily controlled. It is suggested that the sclerotherapy with EO might be a safe, effective, well-tolerated treatment for symptomatic hepatic or renal cysts.

PURPOSE To identify the drug infusion vessel for use in obtaining the best drug distribution in arterial infusion chemotherapy for advanced pancreatic cancer. MATERIALS AND METHODS In 16 cases of advanced pancreatic cancer (pancreatic head, n = 12; pancreatic body and/or tail, n = 4), computed tomography during arterial injection of contrast material was performed at the time of angiography. The sites of catheter placement were celiac artery, superior mesenteric artery, and their branches, such as gastroduodenal artery, inferior pancreatico-duodenal artery, or dorsal pancreatic artery. RESULTS In the cases of pancreatic head cancer, all except one with hepatomesenteric vascular variation were supplied by the celiac artery and superior mesenteric artery (dual supply). In the cases of pancreatic body and/or tail cancer, two were supplied by celiac artery alone and two showed dual supply. In the cases of pancreatic head cancer, when the areas supplied by the main trunk were compared with those supplied by its branches, three of nine cases on the celiac artery side and four cases on the superior mesenteric artery side showed that the areas were not consistent, with a partial defect observed in the areas supplied by branches of the superior mesenteric artery. In the cases of pancreatic body and/or tail cancer, on both sides, one of two cases was not consistent. CONCLUSION To achieve optimal drug distribution in arterial infusion chemotherapy for advanced pancreatic cancer, drug infusion via both the celiac artery and superior mesenteric artery is required in the majority of cases. In many cases, optimal drug distribution is not attainable with drug infusion via a branch; therefore, drug infusion should be administered via the main trunk.

A 26-year-old man developed progressive, massive ascites and hematemesis due to rupture of esophageal varices. Combination diagnostic modalities of color doppler ultrasonography, enhanced computed tomography, and magnetic resonance imaging led to the case being diagnosed as acute Budd-Chiari syndrome with severe stricture of the intrahepatic inferior vena cava. Percutaneous transluminal angioplasty this resulted in great improvement of the clinical manifestations.

Purpose: To evaluate the feasibility and efficacy of a newly designed stent-graft placed across the renal arteries for exclusion of abdominal aortic aneurysms (AAAs) with short or tortuous proximal necks. Methods: Among a group of AAA patients treated with endovascular grafting, 5 had tortuous proximal necks and 13 had necks Results: The stent-grafts were correctly placed at the intended site in all 18 patients. Renal function was not affected except transiently in 1 patient who developed bilateral renal artery stenoses 24 hours after the procedure; Palmaz stents were deployed in each renal artery to reestablish satisfactory blood flow. Of the 33 renal arteries crossed by the bare stent-graft segment, all were patent over a mean 14-month follow-up (range 7–24), including the patient with Palmaz stents implanted for postprocedural renal stenosis. Complete aneurysm exclusion was maintained in 15 (83%) of 18 patients; proximal leaks persisted in 3 patients, including 2 with severely angled proximal necks. Conclusions: Transrenal placement of the uncovered leading edge of custom-made spiral Z-stent—based endografts appears feasible and clinically effective in the treatment of AAAs with short or tortuous proximal necks.

Purpose This study evaluates the relationship between the therapeutic effect of arterial infusion therapy for severe acute pancreatitis and drug distribution on CT-arteriography (CTA). Materials and Methods Eleven patients with severe acute pancreatitis were treated by arterial infusion with use of protease inhibitor and antibiotics. Ten patients had an inflammation of the entire pancreas, while one had pancreatitis localized to the body and tail of the pancreas. The arterial infusion drugs were infused into the celiac artery, splenic artery, inferior pancreaticoduodenal artery, and common hepatic artery. The drug distributions were evaluated by CTA in 10 patients. The duration of arterial infusion ranged from 3 to 39 days. The relationship between the distribution on the CTA and the change in clinical grading of pancreatitis as evaluated by an APACHE II score was studied. Results Of the nine patients with inflammation of the entire pancreas, six showed the distribution of contrast material to the entire area of pancreatic inflammation (a good distribution) on the CTA, and the remaining three did not show the distribution of contrast material to cover the entire area of pancreatic inflammation (a poor distribution). One patient with localized pancreatitis showed a good distribution. In seven patients with a good distribution, the APACHE II score was decreased from 11.7 points to 4.3 points during follow-up. In the remaining three patients with a poor distribution, the APACHE II score was decreased from 12.3 points to nine points, but was decreased to five points after the additional interventions. One patient without CTA showed a marked improvement in the APACHE II score. No clinically important complications were observed. Conclusion The present study findings suggest that arterial infusion is effective in the treatment of severe acute pancreatitis. A good drug distribution to the area of inflammation is needed to ensure a proper therapeutic effect.

Purpose Segmental transcatheter arterial embolization (TAE) with use of iodized oil mixed with an anticancer drug, followed by injection of gelatin sponge particles, was undertaken to evaluate its antitumor effect and its influence on normal tissue in patients with hepatocellular carcinoma (HCC). Patients and Methods Histologic findings in 12 patients who underwent hepatectomy after segmental TAE were compared with findings on plain radiographs and computed tomographic (CT) scans. Visualization of the portal veins contiguous to the tumor on radiographs and the pattern of iodized oil accumulation in the tumor and vicinity on CT scans after TAE were assessed. Results Complete necrosis of the tumor was achieved in 10 cases (83%), while complete necrosis of daughter nodules and capsular invasion was observed histologically in eight of these 10 patients (80%). The degree of tumor necrosis correlated with the pattern of iodized oil accumulation in and near the tumor. Partial necrosis of normal tissue near the tumor correlated with accumulation of iodized oil. Conclusion Segmental TAE may be an excellent therapeutic method for treatment of HCC that is localized in one or a few segmental or sub-segmental regions.

A 26-year-old male was admitted to our hospital having suffered from subfever, sterile pyuria and renal insufficiency for 1 year. There had been no apparent hematuria/proteinuria, and evidence of infection, allergy or intoxication was not demonstrated. Open renal biopsy revealed severe tubulointerstitial changes with granuloma accompanied by neither caseous necrosis nor giant cells. Infiltrating cells mostly consisted of CD4 and CD8 T cells, and some proximal tubular cells presented MHC class II antigen. Following the negative culture of biopsied specimen for acid-fast bacilli, diagnosis of idiopathic granulomatous tubulointerstitial nephritis was made, and steroid therapy was started. Two months later, pyuria disappeared and renal function improved significantly, proving the effectiveness of steroid on idiopathic granulomatous tubulointerstitial nephritis.

A patient with atrophic unilateral hydronephrosis due to ureteropelvic junction obstruction associated with hypertension was successfully treated by nephrectomy. Preoperatively, plasma renin activity was elevated in both the peripheral vein and affected renal vein. Renin concentration in the resected kidney was high, and immunohistochemical localization of renin was observed along the afferent arterioles of the juxtaglomerular apparatus and in arterioles at some distance from the glomeruli.

The so-called embryonal hyperplasia of Bowman's capsular epithelium (EHBCE) is a rather specific lesion occurring in kidneys of patients maintained on chronic dialysis. It consists of poorly differentiated cells proliferating around sclerosed or obsolescent glomeruli. In this study, immunohistochemical and ultrastructural characterization of EHBCE was performed. The poorly differentiated cells in the lesion exhibited a positive reaction for vimentin and a negative one for cytokeratin (PKK 1) and epithelial membrane antigen. On ultrastructural examination, specialized junctions between adjoining cells, microvilli-like structures on their surfaces, and immature basal folds were observed. These observations suggest that the cells of EHBCE may be associated with the anlage of glomerular epithelium. The background in which neoplasms like renal cell carcinoma or atypical epithelium of cyst wall develop in end-stage kidneys of adult patients on long-term dialysis may cause such a proliferation of poorly differentiated cells in young or paediatric age group patients.

A 41-year-old Japanese woman with lipoprotein glomerulopathy is reported. The patient presented with nephrotic syndrome, hyperlipoproteinemia and an increased level of plasma Apo E. The damaged glomeruli showed various degrees of capillary dilatation and accumulation of some material-often showing stratification, along with mesangial proliferation and mesangial interposition. The accumulated material was stained positive for beta-lipoprotein by the indirect immunoperoxidase technique. Capillary dilatation resulted from gradual accumulation of the lipoprotein as well as destruction of the mesangium, as if being torn off, due to increased intraluminal pressure. The patient's eldest sister also suffers from the same renal disease, suggesting a hereditary predisposition.

An autopsy case of an elderly man with Takayasu's arteritis and atherosclerosis is presented. Ischemic signs and symptoms including anginal attack were aggravated with activity of arteritis despite administration of prednisolone throughout the entire course. The autopsy revealed severe atherosclerosis over the aorta and its branches, and arteritis in the fibrotic stage in localized area. Vessels of vital organs including heart and kidneys, did not show Takayasu's arteritis but were atherosclerotic. This case highlights the numerous problems encountered in the treatment of elderly patients with vasculitis such as Takayasu's arteritis.

A paediatric case of lipoprotein glomerulopathy, a new kidney disease characterized by glomerular lipoprotein thrombi, is reported. The patient had massive proteinuria from the age of 8 years, when the nephrotic syndrome was first detected. This was resistant to conventional treatment for more than 10 years. During the course of the disease, the hyperlipidaemia characteristic of hyper-pre-beta-lipoproteinaemia and elevation of apoprotein E persisted, and renal function gradually deteriorated. The renal histopathological findings from four biopsies were essentially the same, with storage of beta-lipoprotein in dilated, balloon-like glomerular capillary lumina. However, the number of glomeruli showing global sclerosis increased and tubulo-interstitial changes progressed in parallel with the gradual clinical deterioration. As in other cases reported in Japan some familial involvement has been noted.

症例は51才女性,急性および慢性腎炎,ネフローゼ症候群の既往がある.昭和54年,慢性腎不全および血清,尿中のλ型Bence Jones蛋白を指摘され,骨シンチグラフィーでは肋骨に異常集積をみたが,骨髓所見に異常はなかつた. 1年半後血液透析を開始,以後4年半にわた無症状で経過した.昭和60年末より左上腕痛,右腓骨神経麻痺,右鎖骨骨折,左動眼神経麻痺を相次いで起こし入院.左脳底部を含めて全身に骨髓腫病変を認め,化学療法と局所放射線照射を行った.眼球運動の改善はみたが全身状態は改善せず,昭和61年7月死亡した.

This report concerns a 41-year-old man with total lipodystrophy associated with a specific renal disorder. He had massive proteinuria, mild azotemia and a normal level of serum complement in addition to the generalized loss of subcutaneous fatty tissue. Results of a 50-gm glucose tolerance test indicated a high fasting insulin level with an exaggerated response to glucose. Hypoglycemic responses to exogenous insulin were reduced. Renal biopsy revealed changes consistent with glomerular lipidosis. This case is unique in that the renal lesion was not the Kimmelstiel-Wilson pathologic change attributable to abnormal glucose metabolism.

Clinicopathological studies of 89 cases of idiopathic membranous glomerulonephritis was carried out to investigate the clinical and histopathological characteristics of the disease. The results were compared with those of previous published reports to observe whether any difference between Japanese and caucasian patients exists. There were no obvious differences as to main clinical features, although an apparently better prognosis in our data was observed during long term follow up. In renal biopsy findings, especially glomerular capillary wall injuries, the prevalence of advanced electron microscopic stages (stages III and IV) was higher in the Japanese cases. A higher rate of clinical remission was observed in the treated group. It was concluded that Japanese cases had an obviously better prognosis despite having more advanced histological findings than the caucasian patients.

An unusual nephropathy presumably induced by abnormal lipid metabolism is described in a 57-year-old woman who presented with proteinuria and edema. Histology at renal biopsy was characterized by marked dilatation of capillary lumina. Sudan staining and electron microscopy demonstrated lipid droplets occupying the capillary lumina. The patient had no particular clinical symptoms of lipidosis, but hyperlipoproteinemia similar to type III was suggested by lipid profiles. The nephropathy is thought to be an inherited disorder because proteinuria was detected in her sisters and similar renal histology and lipid profile were observed in one of her sisters. This is believed to be the first detailed report of glomerular lipoprotein thrombi.